Oral phenylephrine removal from OTC nasal decongestants: next steps for sponsors

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

On November 7, 2024, the FDA published a proposed order that, if finalized, will remove phenylephrine as an active ingredient from orally administered nasal decongestant over-the-counter (OTC) products¹. FDA’s position is that recent review of the available data shows that the drug lacks efficacy for its currently labelled OTC use as a nasal decongestant when administered orally². 

This blog discusses the impact of the FDA’s proposed order on drug sponsors. 

Background 

FDA’s proposed order includes phenylephrine products authorized under the OTC drug review (OTC monograph) process and not the New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) ones.  

Under OTC Monograph M012, oral phenylephrine is listed as an OTC nasal decongestant used in cold, cough, allergy, bronchodilator, and anti-asthmatic drug products. Since 1976, under the current OTC monograph and based on expert review of published literature, the FDA has deemed oral phenylephrine to be generally recognized as safe and effective (GRASE) as an oral nasal decongestant.   

In 2006, phenylephrine became the primary oral decongestant in OTC preparations following the enactment of a law that banned OTC sales of cold medicines containing pseudoephedrine, ephedrine, and phenylpropanolamine; and limited their sale to behind the counter only because of illegal use as starting materials for illicit synthesis of methamphetamine.³ 

How will the changes impact oral phenylephrine sponsors? 

Since 2007, there have been public petitions and FDA advisory committee meetings about the adequacy of evidence in support of the efficacy of oral phenylephrine as a decongestant. In late 2024, FDA held its second Nonprescription Drug Advisory Committee meeting to discuss the GRASE status of oral phenylephrine as a nasal decongestant. Following a comprehensive review, they unanimously concluded that the current scientific data do not support the effectiveness of orally administered phenylephrine as a nasal decongestant.⁴ 

If a final order is issued, oral administration of phenylephrine would not be deemed GRASE. Any oral nasal decongestant product containing it as an ingredient would be considered misbranded under section 502(e) of the FD&C Act. Sponsors of oral OTC products containing phenylephrine would therefore have to voluntarily discontinue distribution and sale. 

Actions for sponsors to take 

We expect the proposed order to become final, based on the FDA’s description of its assessment of the available clinical data. We also expect the agency to provide a sufficient grace period for sponsors to remove their product from the market or reformulate, so as not to disrupt consumers. Timing of the grace period is not yet clear but here we illustrate a previous example that could be informative:   

Pseudoephedrine (2006) case study  

Sponsors were given almost seven months to act when the sale of OTC products containing pseudoephedrine was banned.³ However, the current situation differs in that: 

• Although phenylephrine has proven ineffective as an oral nasal decongestant, it does not present a safety issue.  
• When the sale of pseudoephedrine-containing OTC products was banned, OTC oral nasal decongestants containing phenylephrine were available as alternatives. With phenylephrine removal, no other OTC oral nasal decongestants will be available on the market.  

The final order would only affect drug products marketed under the OTC monograph. However, we anticipate FDA will also request applicants of oral phenylephrine-containing OTC products marketed under the drug application process (i.e., under an approved NDA or ANDA) to withdraw their products from the market. FDA would likely provide the same grace period for products marketed under the drug application process as those marketed under the OTC monograph.     

Therefore, sponsors of OTC oral phenylephrine, brought to market through either the OTC monograph process or drug application process, must choose from the following options:  

1. Reformulation (multi-ingredient products) 

There are several phenylephrine-containing OTC decongestant products containing multiple active ingredients, such as acetaminophen, dextromethorphan, and/or diphenhydramine.    

Reformulation is a major quality change to a product. It ensures that any qualitative/quantitative changes to excipients do not impact the excipient compatibility with active ingredients, nor impact critical quality attributes (CQAs) or critical process parameters (CPPs) which could affect the overall quality (and potentially efficacy and safety) of the drug product. Sponsors could reformulate to remove the quantity of phenylephrine – with overall weight reduction in the case of solid dosage forms (such as tablets or capsules).  

Alternatively, reformulation involves the replacement of the phenylephrine with an inert ingredient such as a diluent filler. Either approach would likely necessitate demonstration of no impact on overall product quality, including comparative dissolution testing to ensure removal of phenylephrine or its replacement with an inert filler does not affect the release of other active ingredients in the product.  

Reformulation as described above for an OTC product initially marketed under the OTC monograph M012 would not require marketing pre-clearance (i.e., submission of a marketing application) after the final order is issued as long as the standards of the final OTC Monograph M012 are met.5  However, sponsors of products marketed under the drug application process, if interested in reformulation, have to submit a prior approval supplement to their application. 

2. Removal from the market (single ingredient products) 

Sponsors of OTC products containing oral phenylephrine as the sole active ingredient would likely have to be removed from the market. However, they could also evaluate and start early planning for the potential adoption of other products to retain a suitable market share in the same OTC therapeutic area.   

2.1 Commercially prioritize other products for nasal congestion 

Sponsors of phenylephrine-containing OTC oral nasal decongestants may already be sponsors for some of the clinical alternatives, which may be recommended by pharmacists for nasal congestion: 

• Topical intranasally administered phenylephrine: Provides local action for nasal congestion relief. 
• Topical intranasally administered decongestants of the imidazole type: Examples include oxymetazoline, which is effective for nasal congestion.  
• Nasal sprays containing corticosteroids or antihistamines: useful for cases of allergic rhinitis. 

Steps for evaluation for commercial prioritization, and marketing strategy include: 

• Clinical review of alternatives: 
  • Conduct a thorough clinical review of the alternatives to determine their efficacy and safety profiles. 
  • Identify which alternatives are most likely to be recommended by pharmacists and physicians. 
• Market access review: 
  • Perform a market access review to understand the commercial potential of these alternatives. 
  • Assess the competitive landscape and potential market share. 
• Pharmaceutical development: 
  • If deciding to market a new product, initiate pharmaceutical development work, including formulation and process development studies. 
  • Conduct scale-up studies to ensure manufacturing feasibility. 
• Acquisition of existing marketed products: 
  • Consider acquiring an existing marketed product to quickly enter the market. 
  • Perform due diligence from both marketing and business perspectives to ensure long-term profitability.  
  • Include Chemistry, Manufacturing, and Controls (CMC) activities to ensure a smooth transfer of formulation and manufacturing processes. 

A multidisciplinary approach is essential to retain market share for OTC consumer health products in the nasal decongestant category. This includes clinical reviews, market access evaluations, pharmaceutical development, and potential acquisition strategies. 

Should we expect a cascade effect for other regulators? 

FDA’s proposed order increases the focus for regulators in other regions to reevaluate the efficacy (and risk/benefit) of oral OTC products containing phenylephrine. 

In Europe, a referral procedure may be initiated to request that the European Medicines Agency (EMA) assess the effectiveness of oral phenylephrine-containing products and make a recommendation.6 This is like the EMA initiation of Article 31 referral procedure in 2011 for oral ketoconazole, an antifungal medication. Although that referral was triggered by concerns about the drug's liver toxicity, its efficacy in treating fungal infections was also scrutinized. The Committee for Medicinal Products for Human Use (CHMP) concluded that the risk of liver injury was higher than the benefits of treating fungal infections, especially given that alternative antifungal treatments were available. Importantly, the committee found the evidence supporting the drug's efficacy in treating fungal infections was limited. As a result of this review, in July 2013, the EMA recommended suspending the marketing authorizations for oral ketoconazole throughout the European Union (EU). This recommendation led to the immediate suspension of oral ketoconazole for systemic use in treating fungal infections across the EU. 

EMA has been evaluating the consumer therapeutic area of OTC decongestants. Specifically, the agency has been assessing the safety of pseudoephedrine, which is still available on the European market as an alternative oral nasal decongestant – in contrast to the US where it has been banned, as discussed above. An Article 31 referral procedure initiated by EMA 7 resulted in CHMP’s confirmation that medicines containing pseudoephedrine should not be used in certain patients with high blood pressure or kidney disease and to minimize the risks associated with pseudoephedrine containing medicines, such as developing posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS). 

Conclusion 

Sponsors of phenylephrine-containing oral decongestant products should follow FDA’s subsequent actions closely and start contingency planning as soon as possible. Reformulation is a challenging process; therefore, several important marketing and clinical aspects need to be considered before pursuing this approach. There are also clinical alternatives and other commercial pathways that could be considered. Sponsors may evaluate developing products with alternative nasal decongestants to retain market share or even acquire an existing marketed product.  

Within Parexel Regulatory Consulting our CMC, clinical, and regulatory colleagues have deep knowledge of the nasal congestion therapeutic area and associated dosage forms. Our Access Consulting team can help you build the complete landscape assessment and evidence package that HTAs and payers require, from the outset.  

To discuss how your oral phenylephrine product could be impacted by FDA’s proposed order and how best to develop a contingency plan to mitigate the regulatory and commercial impact; please get in touch by clicking the button below. Additionally, our subject matter experts understand requirements in all geographical regions should a regulator cascade effect emerge and are always available for a conversation.   

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References 

1. Amending Over-the-Counter Monograph M012: Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use | FDA 
2. Over-the-Counter Monograph M012: Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use (OTC Monograph M012) 
3. Legal Requirements for the Sale and Purchase of Drug Products Containing Pseudoephedrine, Ephedrine, and Phenylpropanolamine 
4. FDA clarifies results of recent advisory committee meeting on oral phenylephrine. 
5. Small Business Assistance: Frequently Asked Questions on the Regulatory Process of Over-the-Counter (OTC) Drugs  
6. Referral procedures: human medicines (EMA Website)  
7. Pseudoephedrine-containing medicinal products – referral (EMA website) 

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